Gel matrix consisting of polyacrylic acid and polyvinyl pyrrolidone

ABSTRACT

A self-adhesive polyacrylic acid-based gel matrix. The gel matrix comprises a homopolymer and/or copolymer of vinyl pyrrolidone as crosslinker for the polyacrylic acid.

The invention relates to a self-adhesive gel matrix, in particular amonolithic gel matrix, which is based on polyacrylic acid and comprisespolyvinylpyrrolidone (PVP) as crosslinking agent. The gel matrix can bedoped with hydrophilic, and hydrophobic with a suitable solubilizer,active ingredients for the cosmetic and/or pharmaceutical treatment ofthe skin or systemic administration of medicaments.

The production of gel matrices from polyacrylates has been known formany years and is described for example in EP 0 507 160, JP 11-228340and JP 04178323. Gel matrices are employed inter alia as adhesive baseand active ingredient reservoir in transdermal systems. An embodiment oftransdermal systems which is well described in the specialist literatureis represented by matrix systems or monolithic systems in which themedicinal substance is incorporated directly into the pressure-sensitiveadhesive. Such a pressure-sensitive adhesive, activeingredient-containing matrix is provided, in the product ready for use,on one side with a backing which is impermeable to the activeingredient, and on the opposite side there is a backing film which isprovided with a separating layer and is removed before application tothe skin (kleben&dichten, No. 42, 1998, pp. 26 to 30). However, thedescribed matrices usually have only low intrinsic adhesiveness, so thatan additional adhesive application aid is necessary for permanentfixation to the skin. Or the systems have sufficient adhesiveness,specifically to moist skin (buccal patch), but cannot be detached againcompletely when required because of inadequate cohesiveness.

Polyacrylic acid must be crosslinked to form a gel of defined structure.The nature of the crosslinker makes a crucial contribution to thestructure of the resulting gel in this case. The usual crosslinkingagents may in this connection be metal ions (e.g. Al³⁺ ions), or organiccompounds. Crosslinking with aluminum salts proceeds via coordination ofthe oxygen functions of the polyacrylic acid to the Al³⁺ ions. A veryclose-mesh gel with high viscosity is formed, it being possible tocontrol the viscosity of the gel only via the amount of crosslinker(handbook of pressure sensitive adhesive technology, page 458 et seq.,1999).

JP 11-228340 discloses polyacrylic acid-based gels which utilize Al³⁺compounds as crosslinkers. Use of the obligatorily necessary aluminumcompound as crosslinking agent is limited because, otherwise, thephysical properties of the gel deteriorate. The gel becomes too hard ifthe content of aluminum crosslinker is too high.

Further examples of crosslinking with multivalent metal ions are knownfrom the literature, e.g. U.S. Pat. No. 3,900,610 (zinc salts), U.S.Pat. No. 3,770,780 or U.S. Pat. No. 3,790,533 (titanium compounds).Ionic crosslinking with metal ions leads to hard, viscous and low-tackpolymer gels (handbook of pressure sensitive adhesive technology, page458 et seq., 1999).

A further problem in the crosslinking of polyacrylic acid to give aself-adhesive gel is that a gel once produced with defined physicalproperties, viscosity, tack etc., must display the same definedproperties in a later production process. This reproducibility is costlyto achieve, if at all, with the currently known crosslinkingtechnologies.

EP 303445 discloses a patch with monolithic gel matrix based onwater-soluble polymers. The obligatorily necessary components which areprovided are clebopride or a pharmaceutically acceptable salt thereof asactive ingredient, water, water-absorbing agents and water-solublepolymers. The skilled worker is able to select water-soluble polymersfrom a number of known polymers such as polyvinyl alcohol, gelatin,polyacrylic acid, sodium polyacrylates, methylcellulose,carboxymethylcellulose, polyvinylpyrrolidone, gum and othercrosslinkable polymers, and mixtures thereof.

A difference from the gel matrix of the invention is that PVP isdisclosed as one possibility for the water-soluble polymer, but not ascrosslinker for polyacrylic acid-based self-adhesive gels. A problemalso described in EP 303445 is the reduction in viscosity and loss ofadhesiveness of the polymers through changing the composition,especially the crosslinking agent.

It is an object of the invention to avoid the disadvantages known in theprior art and provide a self-adhesive gel matrix whose tack,cohesiveness and viscosity can be adjusted individually for theparticular area of application. The particular object of the inventionis to provide a self-adhesive gel matrix for transdermal systems whichcombines the adhesiveness necessary for a monolithic patch applicationwith the appropriate cohesiveness.

This object is achieved by a gel matrix as set forth in claim 1. Thedependent claims relate to advantageous further developments of the gelmatrix.

In the gel matrix of the invention, the crosslinking of the polyacrylicacid is carried out with the aid of polyvinylpyrrolidone (PVP).

The crosslinking proceeds via formation of a quaternary ammonium salt ofPVP. This type of crosslinking leads to organic salts which, in contrastto known metal salts as crosslinking agents, are linked via the hydroxyfunctions of the polyacrylic acid molecules. As with the metal salts,the reaction is reversible and can be reversed through addition of wateror acids. Surprisingly, the viscosity of the resulting gel can becontrolled not only via the amount of crosslinker but also via themolecular weight of the PVP. In this connection, high molecular weightslead to gels of low viscosity and low molecular weights lead to gels ofhigh viscosity and adhesiveness. The advantage of the mode ofcrosslinking according to the invention is thus the targeted production,via the parameters of PVP content and PVP molecular weight, of gelmatrices whose tack, cohesiveness and viscosity can be adjustedindividually for the particular area of application.

This effect of the influence of the PVP molecular weight on theviscosity and adhesiveness of the gel matrix is attributable to thefollowing realization: the number of pyrrolidone subunits permacromolecule is distinctly higher in long-chain PVP than in short-chainPVP. This results in an increase in reactions of identical reactantswith one another, because the macromolecules can easily align to formbundles. These reactions do not lead to a formation of linkage pointswith a plurality of polyacrylic acid molecules. Therefore only a fewcrosslinks are formed with other polyacrylic acid molecules, and thusonly a few, large meshes are formed. This circumstance leads to aloosely linked gel of low viscosity. In contrast thereto, in the case ofshort-chain PVP, because of the greater mobility and the smallertendency of the molecules to align to form strands, more linkages withdifferent polyacrylic acid molecules are formed and lead to a narrowermesh width and lower flexibility and viscosity of the gel.

The viscosity of the gels can additionally be controlled via otherfactors. Thus, for example, the amount of PVP contributes to determiningthe structure of the gel. If a saturation point is exceeded, competingreactions of the free PVP with those already crosslinked occur. Thesecompeting reactions lead to crosslinkage points being broken open infavor of unlinked aggregates of polyacrylic acid and the excess PVPmolecules. The consequence of this supersaturation is a decrease in thetotal number of linkage points and thus a decrease in the gel viscosity.A further possibility which can be utilized for controlling the gelviscosity is to add protic solvents (e.g. water, alcohols, amines,thiols) or organic proton donors (carboxylic acids e.g. salicylic acid)or inorganic agents (e.g. Lewis acids). Specifically suitable for thisare compounds from the families of tertiary polyamines and polyamides.In each of these cases, addition of the agents contributes to reducingthe coordination points either on the polyacrylic acid or on the PVP.This reduces the number of potential linkage points for forming gelmeshes, thus directly influencing the viscosity of the gel.

The resulting gel properties of the matrices can additionally beinfluenced via the molecular weight, degree of substitution and degreeof crosslinking of the polyacrylic acid employed.

To produce particular application properties, the gel matrices are mixedwith the appropriate plasticizers, solubilizers, penetration enhancers,fillers and/or other known additives.

Polyacrylic acid is employed as gel base. Polyacrylates are gel-formingpolymers which can be used advantageously for the purposes of thepresent invention. Polyacrylates which are advantageous according to theinvention are acrylates/alkyl acrylate copolymers, especially thosechosen from the group of so-called carbomers or Carbopols (Carbopol® isactually a registered trademark of the B.F. Goodrich company). Theacrylate/alkyl acrylate copolymer(s) advantageous according to theinvention have the following structure in particular:

In this, R′ is a long-chain alkyl radical and x and y are numbers whichsymbolize the respective stoichiometric content of the respectivecomonomers.

Particularly preferred according to the invention are acrylatecopolymers and acrylate/alkyl acrylate copolymers, which are obtainableunder the proprietary names Carbopol® 1382, Carbopol® 981 and Carbopol®5984 from the B.F. Goodrich company, preferably polyacrylates from thegroup of the Carbopols of the 980, 981, 1382, 2984, 5984 types andparticularly preferably carbomer 2001.

Also advantageous are copolymers of C₁₀₋₃₀-alkyl acrylates and one ormore monomers of acrylic acid, of methacrylic acid or esters thereof,which are crosslinked with an allyl ether of sucrose or an allyl etherof pentaerythritol.

Polyacrylic acid and/or copolymers thereof are preferably employed in anamount of 5-55% by weight, particularly preferably between 5-30% byweight. All percentage data are based in this connection on contents ofgel matrix by weight, unless the opposite is indicated.

The crosslinker employed is polyvinylpyrrolidone (PVP), e.g. Luviskolfrom BASF, preferably in an amount of 0.25-60% by weight, particularlypreferably between 1-30% by weight. It is also possible to the sameextent to employ PVP copolymers such as, for example,vinylpyrrolidone/vinyl acetate (povidone acetate; Kollidon VA 64),terpolymers based on vinylpyrrolidone and acrylic acid or methacrylicacid and esters thereof (Luviflex VBM 35), copolymers ofvinylpyrrolidone and vinylimidazolium methochloride (Luviquat brands) asso-called PVP crosslinking agent.

Further constituents of the gel which can be employed are polyalcohol orpolyalcohols, e.g. 1,2-propanediol, glycerol, and/or water, preferablyin an amount of 5-90% by weight, particularly preferably between 5-45%by weight.

Further constituents of the gel matrix may be stabilizers, e.g.polyethylene glycols (Lutrol E400, E600 from BASF) in an amount of 0-50%by weight, preferably 0-30% by weight, neutralizers, e.g. tromethamol,triethanolamine and/or dexpanthenol, in an amount 0-30% by weight,preferably 0-15% by weight, filler(s), e.g. silica, micronized celluloseand/or gelatin, in an amount of 0-30% by weight, preferably 3-15% byweight, and natural active ingredient(s), e.g. menthol, jojoba oil,ibuprofen, benzyl nicotinate and/or capsaicin, in an amount of 0-35% byweight, preferably 0-15% by weight.

These gel matrices are produced without solvent, preferably at roomtemperature, in commercially available kneaders or suitable extruders.The polyacrylic acid-based gel matrix of the invention combines thenecessary adhesiveness with the appropriate cohesiveness for amonolithic patch application. For application as patches, the gelmatrices are pressed, rolled or the like as layer onto a separatingmedium of paper, film or the like, and laminated on the reverse sidewith any desired backing material.

The gel matrix of the invention is particularly advantageously appliedto a flexible cover layer, especially for use as patch. An appropriatepatch is composed of a backing such as films, nonwovens, wovens, foamsetc., the adhesive matrix and covering film, covering paper orseparating paper to protect the adhesive matrix before use of the patch.

In a further preferred embodiment of the invention, polymer films,nonwovens, wovens and combinations thereof are employed as backing.Available for selection as backing materials are, inter alia, polymerssuch as polyethylene, polypropylene and polyurethane or else naturalfibers.

In summary, it can be stated that all rigid and elastic sheet-likestructures of synthetic and natural raw materials are suitable asbacking materials. Preferred backing materials are those which can beemployed in such a way that they comply with the properties of theproperly functioning dressing. Examples listed are textiles such aswovens, knits, lace, nonwovens, laminates, nets, films, foams andpapers. In addition, these materials can be pretreated or aftertreated.Conventional pretreatments are corona and hydrophobias; customaryaftertreatments are calendering, heat treatment, laminating, punchingand lining.

It is particularly advantageous for the carrier material to besterilizable, preferably γ (gamma) sterlizable.

Said properties of the adhesive matrix suggest in particular the use formedical products, especially patches, medical fixings, wound coverings,orthopedic and phlebological bandages and dressings.

Finally, the gel matrix can be lined with an adhesive-repellent backingmaterial such as siliconized paper or be provided with a wound pad or acushion. The patch of the invention is normally covered on its sidewhich has a self-adhesive finish and later faces the skin over its wholewidth until used with an adhesive-repellent backing material. Thisprotects the self-adhesive layer from the gel matrix adhesivecomposition, which is well tolerated by skin and has preferably beenapplied by a transfer process, and additionally stabilizes the wholeproduct. The covering can be designed in a known manner to be in onepiece or, preferably, in two parts.

Further embodiments may be configured so that a second matrix withhigher active ingredient solubility is present as reservoir between thereverse side of the matrix and the covering backing. This might be,instead of a second matrix and backing, also a thermoformed film withpure active ingredient.

On part (e.g. at the edge) of the adhesive side of the matrix there is asecond matrix with high adhesiveness for additional fixation, butinadequate active ingredient solubility.

The active ingredient-free matrix is located between two non-anchoringfilms and is used for the fixation of electrodes etc., or, because ofthe water uptake capacity, with an appropriate geometry ofcolostomy/ileostomy bags. The active ingredient-free matrix may alsoserve (with or without wound pad) as adhesive layer for a simplewound/adhesive plaster.

The following examples illustrate the invention without restricting it.The gel matrices of the invention are listed in the following table.

EXAMPLES 1 to 9

Constituents/Example 1 2 3 4 5 6 7 8 9 Polyacrylic acid 22.5% 18.0%22.5% 22.5% 22.5% 22.5% 22.5% 21.0% 21.0% Polyvinylpyrrolidone  3.5% 3.5%  3.5%  3.5%  3.5%  3.5%  3.5%  3.5%  3.5% PVP 25 Propanediol 36.0%43.5% 36.5% 37.5% 35.5% 25.5% 40.0% 35.5% 35.5% Polyethylene glycol17.0% 23.5% 17.0%  6.5% 20.0% 12.0% 21.0% 20.0% 20.0% Silica  8.0%  5.0%10.0% 10.0% 11.5% 11.5% 10.0% 10.0% 10.0% Dexpanthenol  5.0%  5.0%  5.0% 5.0%  5.0%  5.0% —  5.0%  5.0% Jojoba oil  5.0%  0.5%  5.0%  5.0% — — —— — Salicylic acid  3.0%  1.0% — — — —  3.0% — — Benzyl nicotinate — — 0.5% — — — — — — Glycol salicylate — — — 10.0% — 10.0% — — — Menthol —— — —  2.0% — — — — Peppermint oil — — — — — 10.0% — — — Ibuprofen — — —— — — —  5.0% — Tea tree oil — — — — — — — —  5.0%

EXAMPLES 10 to 18

Constituents/Examples 10 11 12 13 14 15 16 17 18 Polyacrylic acid  5.0%10.5% 10.5% 21.0% 21.0% 21.0% 10.5% 11.7% 18.0% Polyvinylpyrrolidone30.0%  3.5%  3.5%  3.5%  3.5%  3.5%  3.5%  3.9%  3.5% Propanediol — — 5.0% 35.5% 35.5% 35.5% — — 58.5% Polyethylene glycol — — — 15.0% 20.0%20.0% 20.0% 22.1% — Diethylene glycol 25.0% — — — — — — — — Glycerol —72.47%  77.0% — — — 46.0% 51.1% 10.0% Water 15.0% — — — — — — — —Polyoxyethylene 20 — 10.0% — — — — — — — sorbitan monolaurate Isopropylmyristate — — —  5.0% — — — — — Silica 15.0% — — 10.0% 10.0% 10.0% 10.0%— — Gelatin —  3.5%  3.5% — — — — — — Dexpanthenol — — —  5.0%  5.0% 5.0%  5.0%  5.6%  5.0% Urea 10.0% — — — — — — — — Vitamin A palmitate —0.03% — — — — — — — Capsicum extract — —  0.5%  5.0% — — — — —Clotrimazole — — — —  5.0% — — — — Lidocaine HCl — — — — —  5.0% — — —Ibuprofen — — — — — —  5.0%  5.6%  5.0%

For application as patch, all the gel matrices listed by way of examplehave been rolled as layer onto a separating medium (backing) of paperand film, and their adhesive property and cohesiveness have beenassessed organoleptically. All the patches of the invention differ frompatches with known gels in providing sufficiently good adhesiveness andappropriate cohesiveness, so that all the patches can be detached fromthe skin without residues.

EXAMPLES 19 to 25

In accordance with example 1, the following polyvinylpyrolidones ormixtures thereof are employed in place of polyvinylpyrrolidone PVP 25.Average molecular Example weight [g/mol] 19 PVP 12 ca. 2 500 20 PVP 17ca. 11 500 21 PVP 25 ca. 25 000 22 PVP 30 ca. 40 000 23 PVP 90 ca. 700000 24 PVP 12 and PVP 30, 1:1 ca. 21 250 25 PVP 25 and PVP 90, 1:1 ca.370 000

Example 19, 20, 21 and 24 led to gels whose adhesiveness could beassessed as good or very good and whose cohesiveness could be assessedas adequate. Example 22, 23 and 25 led to gels of low viscosity and lessadhesiveness. The advantage of the mode of crosslinking according to theinvention is thus the specific production, via the parameters of VPcontent and PVP molecular weight, of gel matrices whose tack,cohesiveness and viscosity can be adjusted individually to theparticular area of application.

The advantageous properties of the gel matrices of the invention intransdermal systems are thus impressively confirmed.

1-19. (canceled)
 20. A self-adhesive polyacrylic acid-based gel matrix, wherein the gel matrix comprises at least one of a homopolymer and a copolymer of vinyl pyrrolidone as a crosslinker of the polyacrylic acid.
 21. The gel matrix of claim 20, wherein the polyacrylic acid comprises an acrylates/alkyl acrylate copolymer.
 22. The gel matrix of claim 20, wherein the at least one of a homopolymer and a copolymer of vinyl pyrrolidone is present as a mixture of polymers of different average molecular weights.
 23. The gel matrix of claim 20, wherein the at least one of a homopolymer and a copolymer of vinyl pyrrolidone comprises at least one polymer having an average molecular weight in a range of from 2,500 to 700,000 g/mol.
 24. The gel matrix of claim 20, wherein the gel matrix comprises from 5% to 55% by weight of at least one of a homopolymer and a copolymer of acrylic acid.
 25. The gel matrix of claim 24, wherein the gel matrix comprises up to 30% by weight of the at least one of a homopolymer and a copolymer of acrylic acid.
 26. The gel matrix of claim 20, wherein the gel matrix comprises from 0.25% to 60% by weight of at least one of a homopolymer and a copolymer of vinyl pyrrolidone.
 27. The gel matrix of claim 26, wherein the gel matrix comprises from 1% to 30% by weight of the at least one of a homopolymer and a copolymer of vinyl pyrrolidone.
 28. The gel matrix of claim 20, wherein the gel matrix comprises from 5% to 30% by weight of at least one of a homopolymer and a copolymer of acrylic acid, and from 1% to 30% by weight of at least one of a homopolymer and a copolymer of vinyl pyrrolidone.
 29. The gel matrix of claim 20, wherein the gel matrix further comprises at least one polyalcohol.
 30. The gel matrix of claim 29, wherein the gel matrix comprises at least one of propanediol, polyethylene glycol and glycerol.
 31. The gel matrix of claim 29, wherein the at least one polyalcohol is present in a concentration of from 5% to 90% by weight.
 32. The gel matrix of claim 31, wherein the concentration is up to 45% by weight.
 33. The gel matrix of claim 20, wherein the gel matrix further comprises at least one of a protic solvent, an organic proton donor and a Lewis acid.
 34. The gel matrix of claim 33, wherein the gel matrix comprises at least one of water, an alcohol, an amine and a thiol.
 35. The gel matrix of claim 33, wherein the gel matrix comprises salicylic acid.
 36. The gel matrix of claim 20, wherein the gel matrix is doped with a hydrophilic active ingredient.
 37. The gel matrix of claim 20, wherein the gel matrix is doped with a combination of a hydrophobic active ingredient and a solubilizer.
 38. The gel matrix of claim 20, wherein the gel matrix is doped with at least one of dexpanthenol, jojoba oil, salicylic acid, benzyl nicotinate, glycol salicylate, menthol, peppermint oil, ibuprofen, tea tree oil, urea, vitamin A palmitate, capsicum extract, clotrimazole and lidocaine HCI.
 39. The gel matrix of claim 20, which further comprises at least one of a plasticizer, a solubilizer, a penetration enhancer and a filler.
 40. The gel matrix of claim 20, which comprises from 5% to 30% by weight of at least one of a homopolymer and a copolymer of acrylic acid, from 1% to 30% by weight of at least one of a homopolymer and a copolymer of vinyl pyrrolidone and from 5% to 45% by weight of at least one polyalcohol.
 41. The gel matrix of claim 40, wherein the polyalcohol comprises at least one of propanediol, polyethylene glycol and glycerol.
 42. The gel matrix of claim 41, wherein the gel matrix further comprises at least one of water, an alcohol, an amine and a thiol.
 43. The gel matrix of claim 42, wherein the gel matrix is doped with at least one of a hydrophilic active ingredient and a combination of a hydrophobic active ingredient and a solubilizer.
 44. The gel matrix of claim 41, wherein the gel matrix is doped with at least one of dexpanthenol,jojoba oil, salicylic acid, benzyl nicotinate, glycol salicylate, menthol, peppermint oil, ibuprofen, tea tree oil, urea, vitamin A palmitate, capsicum extract, clotrimazole and lidocaine HCI.
 45. A transdermal system which comprises the gel matrix of claim
 20. 46. The transdermal system of claim 45, wherein the transdermal system comprises a patch.
 47. The transdermal system of claim 46, wherein the patch comprises a backing for the gel matrix and at least one of a covering film, a covering paper and a release paper.
 48. A medical fixing which comprises the gel matrix of claim
 20. 49. A wound covering which comprises the gel matrix of claim
 20. 50. An orthopedic or phlebologic bandage which comprises the gel matrix of claim
 20. 51. A dressing which comprises the gel matrix of claim
 20. 52. A method for the cosmetic or medical treatment of skin, wherein the method comprises applying to at least parts of the skin the gel matrix of claim
 20. 53. A method of controlling at least one of the viscosity and adhesiveness of a self-adhesive polyacrylic acid-based gel matrix, wherein the method comprises combining the gel matrix with at least one of a homopolymer and a copolymer of vinyl pyrrolidone as a crosslinker for the polyacrylic acid.
 54. The method of claim 53, wherein the at least one of the viscosity and adhesiveness are controlled by an amount of the vinyl pyrrolidone polymer.
 55. The method of claim 53, wherein the at least one of the viscosity and adhesiveness are controlled by an average molecular weight of the vinyl pyrrolidone polymer.
 56. A process for producing a self-adhesive polyacrylic acid-based gel matrix, which process comprises mixing at least one of a homopolymer and a copolymer of acrylic acid with at least one of a homopolymer and a copolymer of vinyl pyrrolidone to crosslink the acrylic acid polymer.
 57. The process of claim 56, wherein from 5% to 55% by weight of the at least one of a homopolymer and a copolymer of acrylic acid are employed.
 58. The process of claim 57, wherein up to 30% by weight of the at least one of a homopolymer and a copolymer of acrylic acid are employed.
 59. The process of claim 56, wherein from 0.25% to 60% by weight of the at least one of a homopolymer and a copolymer of vinyl pyrrolidone are employed.
 60. The process of claim 58, wherein from 1% to 30% by weight of the at least one of a homopolymer and a copolymer of vinyl pyrrolidone are employed.
 61. The process of claim 56, wherein further at least one of a polyalcohol and water is employed.
 62. The process of claim 61, wherein the polyalcohol comprises at least one of propanediol, polyethylene glycol and glycerol.
 63. The process of claim 61, wherein the at least one of a polyalcohol and water is employed in an amount of from 5% to 90% by weight.
 64. The process of claim 63, wherein the amount is up to 45% by weight.
 65. The process of claim 56, wherein further at least one of a hydrophilic active ingredient and a combination of a hydrophobic active ingredient and a solubilizer is employed. 